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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1998 Jun 29;353(1370):847–856. doi: 10.1098/rstb.1998.0249

Cellular and molecular partners involved in gut morphogenesis and differentiation.

M Kedinger 1, O Lefebvre 1, I Duluc 1, J N Freund 1, P Simon-Assmann 1
PMCID: PMC1692284  PMID: 9684282

Abstract

The intestinal mucosa represents an interesting model to study the cellular and molecular basis of epithelial-mesenchymal cross-talk participating in the development and maintenance of the digestive function. This cross-talk involves extracellular matrix molecules, cell-cell and cell-matrix adhesion molecules as well as paracrine factors and their receptors. The cellular and molecular unit is additionally regulated by hormonal, immune and neural inputs. Such integrated cell interactions are involved in pattern formation, in proximodistal regionalization, in maintenance of a gradient of epithelial proliferation and differentiation, and in epithelial cell migration. We focus predominantly on two aspects of these integrated interactions in this paper: (i) the role of basement membrane molecules, namely laminins, in the developmental and spatial epithelial behaviour; and (ii) the importance of the mesenchymal cell compartment in these processes.

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Selected References

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  1. Babyatsky M. W., Rossiter G., Podolsky D. K. Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease. Gastroenterology. 1996 Apr;110(4):975–984. doi: 10.1053/gast.1996.v110.pm8613031. [DOI] [PubMed] [Google Scholar]
  2. Beaulieu J. F., Vachon P. H. Reciprocal expression of laminin A-chain isoforms along the crypt-villus axis in the human small intestine. Gastroenterology. 1994 Apr;106(4):829–839. doi: 10.1016/0016-5085(94)90740-4. [DOI] [PubMed] [Google Scholar]
  3. Birchmeier C., Meyer D., Riethmacher D. Factors controlling growth, motility, and morphogenesis of normal and malignant epithelial cells. Int Rev Cytol. 1995;160:221–266. doi: 10.1016/s0074-7696(08)61556-9. [DOI] [PubMed] [Google Scholar]
  4. Bouziges F., Simo P., Simon-Assmann P., Haffen K., Kedinger M. Altered deposition of basement-membrane molecules in co-cultures of colonic cancer cells and fibroblasts. Int J Cancer. 1991 Apr 22;48(1):101–108. doi: 10.1002/ijc.2910480119. [DOI] [PubMed] [Google Scholar]
  5. Brauchle M., Madlener M., Wagner A. D., Angermeyer K., Lauer U., Hofschneider P. H., Gregor M., Werner S. Keratinocyte growth factor is highly overexpressed in inflammatory bowel disease. Am J Pathol. 1996 Aug;149(2):521–529. [PMC free article] [PubMed] [Google Scholar]
  6. Burgeson R. E., Chiquet M., Deutzmann R., Ekblom P., Engel J., Kleinman H., Martin G. R., Meneguzzi G., Paulsson M., Sanes J. A new nomenclature for the laminins. Matrix Biol. 1994 Apr;14(3):209–211. doi: 10.1016/0945-053x(94)90184-8. [DOI] [PubMed] [Google Scholar]
  7. Chantret I., Rodolosse A., Barbat A., Dussaulx E., Brot-Laroche E., Zweibaum A., Rousset M. Differential expression of sucrase-isomaltase in clones isolated from early and late passages of the cell line Caco-2: evidence for glucose-dependent negative regulation. J Cell Sci. 1994 Jan;107(Pt 1):213–225. doi: 10.1242/jcs.107.1.213. [DOI] [PubMed] [Google Scholar]
  8. Chawengsaksophak K., James R., Hammond V. E., Köntgen F., Beck F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature. 1997 Mar 6;386(6620):84–87. doi: 10.1038/386084a0. [DOI] [PubMed] [Google Scholar]
  9. De Arcangelis A., Neuville P., Boukamel R., Lefebvre O., Kedinger M., Simon-Assmann P. Inhibition of laminin alpha 1-chain expression leads to alteration of basement membrane assembly and cell differentiation. J Cell Biol. 1996 Apr;133(2):417–430. doi: 10.1083/jcb.133.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. De Arcangelis A., Simo P., Lesuffleur T., Kedinger M., Simon-Assmann P. L'expression de la laminine est corrélée à la différenciation des cellules cancéreuses coliques humaines. Gastroenterol Clin Biol. 1994;18(6-7):630–637. [PubMed] [Google Scholar]
  11. Duluc I., Freund J. N., Leberquier C., Kedinger M. Fetal endoderm primarily holds the temporal and positional information required for mammalian intestinal development. J Cell Biol. 1994 Jul;126(1):211–221. doi: 10.1083/jcb.126.1.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Duluc I., Lorentz O., Fritsch C., Leberquier C., Kedinger M., Freund J. N. Changing intestinal connective tissue interactions alters homeobox gene expression in epithelial cells. J Cell Sci. 1997 Jun;110(Pt 11):1317–1324. doi: 10.1242/jcs.110.11.1317. [DOI] [PubMed] [Google Scholar]
  13. Dziadek M. Role of laminin-nidogen complexes in basement membrane formation during embryonic development. Experientia. 1995 Sep 29;51(9-10):901–913. doi: 10.1007/BF01921740. [DOI] [PubMed] [Google Scholar]
  14. Ee H. C., Erler T., Bhathal P. S., Young G. P., James R. J. Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma. Am J Pathol. 1995 Sep;147(3):586–592. [PMC free article] [PubMed] [Google Scholar]
  15. Fontao L., Dirrig S., Owaribe K., Kedinger M., Launay J. F. Polarized expression of HD1: relationship with the cytoskeleton in cultured human colonic carcinoma cells. Exp Cell Res. 1997 Mar 15;231(2):319–327. doi: 10.1006/excr.1996.3465. [DOI] [PubMed] [Google Scholar]
  16. Fraichard A., Chassande O., Plateroti M., Roux J. P., Trouillas J., Dehay C., Legrand C., Gauthier K., Kedinger M., Malaval L. The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. EMBO J. 1997 Jul 16;16(14):4412–4420. doi: 10.1093/emboj/16.14.4412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fritsch C., Simon-Assmann P., Kedinger M., Evans G. S. Cytokines modulate fibroblast phenotype and epithelial-stroma interactions in rat intestine. Gastroenterology. 1997 Mar;112(3):826–838. doi: 10.1053/gast.1997.v112.pm9041244. [DOI] [PubMed] [Google Scholar]
  18. Fässler R., Georges-Labouesse E., Hirsch E. Genetic analyses of integrin function in mice. Curr Opin Cell Biol. 1996 Oct;8(5):641–646. doi: 10.1016/s0955-0674(96)80105-0. [DOI] [PubMed] [Google Scholar]
  19. García-Alonso L., Fetter R. D., Goodman C. S. Genetic analysis of Laminin A in Drosophila: extracellular matrix containing laminin A is required for ocellar axon pathfinding. Development. 1996 Sep;122(9):2611–2621. doi: 10.1242/dev.122.9.2611. [DOI] [PubMed] [Google Scholar]
  20. Giannelli G., Falk-Marzillier J., Schiraldi O., Stetler-Stevenson W. G., Quaranta V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science. 1997 Jul 11;277(5323):225–228. doi: 10.1126/science.277.5323.225. [DOI] [PubMed] [Google Scholar]
  21. Griebel P., Hein W. R., Dudler L., Ferrari G. Phenotype and function of stromal cells cloned from the ileal Peyer's patch of sheep. Stem Cells. 1993 Mar;11(2):130–143. doi: 10.1002/stem.5530110208. [DOI] [PubMed] [Google Scholar]
  22. Halttunen T., Marttinen A., Rantala I., Kainulainen H., Mäki M. Fibroblasts and transforming growth factor beta induce organization and differentiation of T84 human epithelial cells. Gastroenterology. 1996 Nov;111(5):1252–1262. doi: 10.1053/gast.1996.v111.pm8898639. [DOI] [PubMed] [Google Scholar]
  23. Henchcliffe C., García-Alonso L., Tang J., Goodman C. S. Genetic analysis of laminin A reveals diverse functions during morphogenesis in Drosophila. Development. 1993 Jun;118(2):325–337. doi: 10.1242/dev.118.2.325. [DOI] [PubMed] [Google Scholar]
  24. Hentsch B., Lyons I., Li R., Hartley L., Lints T. J., Adams J. M., Harvey R. P. Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut. Genes Dev. 1996 Jan 1;10(1):70–79. doi: 10.1101/gad.10.1.70. [DOI] [PubMed] [Google Scholar]
  25. Hirai Y., Takebe K., Takashina M., Kobayashi S., Takeichi M. Epimorphin: a mesenchymal protein essential for epithelial morphogenesis. Cell. 1992 May 1;69(3):471–481. doi: 10.1016/0092-8674(92)90448-l. [DOI] [PubMed] [Google Scholar]
  26. Hogaboam C. M., Snider D. P., Collins S. M. Cytokine modulation of T-lymphocyte activation by intestinal smooth muscle cells. Gastroenterology. 1997 Jun;112(6):1986–1995. doi: 10.1053/gast.1997.v112.pm9178691. [DOI] [PubMed] [Google Scholar]
  27. Iivanainen A., Sainio K., Sariola H., Tryggvason K. Primary structure and expression of a novel human laminin alpha 4 chain. FEBS Lett. 1995 May 29;365(2-3):183–188. doi: 10.1016/0014-5793(95)00462-i. [DOI] [PubMed] [Google Scholar]
  28. James R., Erler T., Kazenwadel J. Structure of the murine homeobox gene cdx-2. Expression in embryonic and adult intestinal epithelium. J Biol Chem. 1994 May 27;269(21):15229–15237. [PubMed] [Google Scholar]
  29. James R., Kazenwadel J. Homeobox gene expression in the intestinal epithelium of adult mice. J Biol Chem. 1991 Feb 15;266(5):3246–3251. [PubMed] [Google Scholar]
  30. Kaestner K. H., Silberg D. G., Traber P. G., Schütz G. The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation. Genes Dev. 1997 Jun 15;11(12):1583–1595. doi: 10.1101/gad.11.12.1583. [DOI] [PubMed] [Google Scholar]
  31. Leivo I., Tani T., Laitinen L., Bruns R., Kivilaakso E., Lehto V. P., Burgeson R. E., Virtanen I. Anchoring complex components laminin-5 and type VII collagen in intestine: association with migrating and differentiating enterocytes. J Histochem Cytochem. 1996 Nov;44(11):1267–1277. doi: 10.1177/44.11.8918902. [DOI] [PubMed] [Google Scholar]
  32. Lorentz O., Duluc I., Arcangelis A. D., Simon-Assmann P., Kedinger M., Freund J. N. Key role of the Cdx2 homeobox gene in extracellular matrix-mediated intestinal cell differentiation. J Cell Biol. 1997 Dec 15;139(6):1553–1565. doi: 10.1083/jcb.139.6.1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Martin M., Pujuguet P., Martin F. Role of stromal myofibroblasts infiltrating colon cancer in tumor invasion. Pathol Res Pract. 1996 Jul;192(7):712–717. doi: 10.1016/S0344-0338(96)80093-8. [DOI] [PubMed] [Google Scholar]
  34. Miner J. H., Patton B. L., Lentz S. I., Gilbert D. J., Snider W. D., Jenkins N. A., Copeland N. G., Sanes J. R. The laminin alpha chains: expression, developmental transitions, and chromosomal locations of alpha1-5, identification of heterotrimeric laminins 8-11, and cloning of a novel alpha3 isoform. J Cell Biol. 1997 May 5;137(3):685–701. doi: 10.1083/jcb.137.3.685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Neuville P., Geinoz A., Benzonana G., Redard M., Gabbiani F., Ropraz P., Gabbiani G. Cellular retinol-binding protein-1 is expressed by distinct subsets of rat arterial smooth muscle cells in vitro and in vivo. Am J Pathol. 1997 Feb;150(2):509–521. [PMC free article] [PubMed] [Google Scholar]
  36. Orian-Rousseau V., Aberdam D., Fontao L., Chevalier L., Meneguzzi G., Kedinger M., Simon-Assmann P. Developmental expression of laminin-5 and HD1 in the intestine: epithelial to mesenchymal shift for the laminin gamma-2 chain subunit deposition. Dev Dyn. 1996 May;206(1):12–23. doi: 10.1002/(SICI)1097-0177(199605)206:1<12::AID-AJA2>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  37. Plateroti M., Freund J. N., Leberquier C., Kedinger M. Mesenchyme-mediated effects of retinoic acid during rat intestinal development. J Cell Sci. 1997 May;110(Pt 10):1227–1238. doi: 10.1242/jcs.110.10.1227. [DOI] [PubMed] [Google Scholar]
  38. Potten C. S., Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development. 1990 Dec;110(4):1001–1020. doi: 10.1242/dev.110.4.1001. [DOI] [PubMed] [Google Scholar]
  39. Pyke C., Salo S., Ralfkiaer E., Rømer J., Danø K., Tryggvason K. Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res. 1995 Sep 15;55(18):4132–4139. [PubMed] [Google Scholar]
  40. Roberts A. I., Nadler S. C., Ebert E. C. Mesenchymal cells stimulate human intestinal intraepithelial lymphocytes. Gastroenterology. 1997 Jul;113(1):144–150. doi: 10.1016/s0016-5085(97)70089-1. [DOI] [PubMed] [Google Scholar]
  41. Rousselle P., Lunstrum G. P., Keene D. R., Burgeson R. E. Kalinin: an epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments. J Cell Biol. 1991 Aug;114(3):567–576. doi: 10.1083/jcb.114.3.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schuler F., Sorokin L. M. Expression of laminin isoforms in mouse myogenic cells in vitro and in vivo. J Cell Sci. 1995 Dec;108(Pt 12):3795–3805. doi: 10.1242/jcs.108.12.3795. [DOI] [PubMed] [Google Scholar]
  43. Silberg D. G., Furth E. E., Taylor J. K., Schuck T., Chiou T., Traber P. G. CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium. Gastroenterology. 1997 Aug;113(2):478–486. doi: 10.1053/gast.1997.v113.pm9247467. [DOI] [PubMed] [Google Scholar]
  44. Simo P., Bouziges F., Lissitzky J. C., Sorokin L., Kedinger M., Simon-Assmann P. Dual and asynchronous deposition of laminin chains at the epithelial-mesenchymal interface in the gut. Gastroenterology. 1992 Jun;102(6):1835–1845. doi: 10.1016/0016-5085(92)90303-g. [DOI] [PubMed] [Google Scholar]
  45. Simo P., Simon-Assmann P., Arnold C., Kedinger M. Mesenchyme-mediated effect of dexamethasone on laminin in cocultures of embryonic gut epithelial cells and mesenchyme-derived cells. J Cell Sci. 1992 Jan;101(Pt 1):161–171. doi: 10.1242/jcs.101.1.161. [DOI] [PubMed] [Google Scholar]
  46. Simo P., Simon-Assmann P., Bouziges F., Leberquier C., Kedinger M., Ekblom P., Sorokin L. Changes in the expression of laminin during intestinal development. Development. 1991 Jun;112(2):477–487. doi: 10.1242/dev.112.2.477. [DOI] [PubMed] [Google Scholar]
  47. Simon-Assmann P., Bouziges F., Arnold C., Haffen K., Kedinger M. Epithelial-mesenchymal interactions in the production of basement membrane components in the gut. Development. 1988 Feb;102(2):339–347. doi: 10.1242/dev.102.2.339. [DOI] [PubMed] [Google Scholar]
  48. Simon-Assmann P., Bouziges F., Freund J. N., Perrin-Schmitt F., Kedinger M. Type IV collagen mRNA accumulates in the mesenchymal compartment at early stages of murine developing intestine. J Cell Biol. 1990 Mar;110(3):849–857. doi: 10.1083/jcb.110.3.849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Simon-Assmann P., Bouziges F., Vigny M., Kedinger M. Origin and deposition of basement membrane heparan sulfate proteoglycan in the developing intestine. J Cell Biol. 1989 Oct;109(4 Pt 1):1837–1848. doi: 10.1083/jcb.109.4.1837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Simon-Assmann P., Duclos B., Orian-Rousseau V., Arnold C., Mathelin C., Engvall E., Kedinger M. Differential expression of laminin isoforms and alpha 6-beta 4 integrin subunits in the developing human and mouse intestine. Dev Dyn. 1994 Sep;201(1):71–85. doi: 10.1002/aja.1002010108. [DOI] [PubMed] [Google Scholar]
  51. Simon-Assmann P., Kedinger M., De Arcangelis A., Rousseau V., Simo P. Extracellular matrix components in intestinal development. Experientia. 1995 Sep 29;51(9-10):883–900. doi: 10.1007/BF01921739. [DOI] [PubMed] [Google Scholar]
  52. Simon-Assmann P., Leberquier C., Molto N., Uezato T., Bouziges F., Kedinger M. Adhesive properties and integrin expression profiles of two colonic cancer populations differing by their spreading on laminin. J Cell Sci. 1994 Mar;107(Pt 3):577–587. doi: 10.1242/jcs.107.3.577. [DOI] [PubMed] [Google Scholar]
  53. Sorokin L. M., Pausch F., Frieser M., Kröger S., Ohage E., Deutzmann R. Developmental regulation of the laminin alpha5 chain suggests a role in epithelial and endothelial cell maturation. Dev Biol. 1997 Sep 15;189(2):285–300. doi: 10.1006/dbio.1997.8668. [DOI] [PubMed] [Google Scholar]
  54. Suh E., Chen L., Taylor J., Traber P. G. A homeodomain protein related to caudal regulates intestine-specific gene transcription. Mol Cell Biol. 1994 Nov;14(11):7340–7351. doi: 10.1128/mcb.14.11.7340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Suh E., Traber P. G. An intestine-specific homeobox gene regulates proliferation and differentiation. Mol Cell Biol. 1996 Feb;16(2):619–625. doi: 10.1128/mcb.16.2.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Uitto J., Pulkkinen L. Molecular complexity of the cutaneous basement membrane zone. Mol Biol Rep. 1996;23(1):35–46. doi: 10.1007/BF00357071. [DOI] [PubMed] [Google Scholar]
  57. Vachon P. H., Beaulieu J. F. Extracellular heterotrimeric laminin promotes differentiation in human enterocytes. Am J Physiol. 1995 May;268(5 Pt 1):G857–G867. doi: 10.1152/ajpgi.1995.268.5.G857. [DOI] [PubMed] [Google Scholar]
  58. Vuolteenaho R., Nissinen M., Sainio K., Byers M., Eddy R., Hirvonen H., Shows T. B., Sariola H., Engvall E., Tryggvason K. Human laminin M chain (merosin): complete primary structure, chromosomal assignment, and expression of the M and A chain in human fetal tissues. J Cell Biol. 1994 Feb;124(3):381–394. doi: 10.1083/jcb.124.3.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Walters J. R., Howard A., Rumble H. E., Prathalingam S. R., Shaw-Smith C. J., Legon S. Differences in expression of homeobox transcription factors in proximal and distal human small intestine. Gastroenterology. 1997 Aug;113(2):472–477. doi: 10.1053/gast.1997.v113.pm9247466. [DOI] [PubMed] [Google Scholar]
  60. Xu H., Christmas P., Wu X. R., Wewer U. M., Engvall E. Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5572–5576. doi: 10.1073/pnas.91.12.5572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yarnitzky T., Volk T. Laminin is required for heart, somatic muscles, and gut development in the Drosophila embryo. Dev Biol. 1995 Jun;169(2):609–618. doi: 10.1006/dbio.1995.1173. [DOI] [PubMed] [Google Scholar]

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